The advantages of employing sustained-release drug implants are well known in the art. Many therapeutic agents are rapidly metabolized or cleared from the mammalian body requiring frequent administration of the drug to maintain adequate therapeutic concentration. There is therefore a need for a sustained release implant capable of administering an active compound at a relatively constant rate at a level sufficient to maintain an effective concentration.
A number of sustained-release implants are known in the art. Some implants are "matrix" type, and comprise an active compound dispersed in a matrix of a carrier material. The carrier material may be either porous or non-porous, solid or semi-solid, and permeable or impermeable to the active compound. Matrix devices may be biodegradable, i.e., they may slowly erode after administration. Alternatively, matrix devices may be nondegradable, and rely on diffusion of the active compound through the walls or pores of the matrix. Matrix devices may be easily prepared, but are not suitable for all compounds. Furthermore, it is difficult to prepare matrix devices that release active compound at a constant rate (i.e., zero order kinetics). Generally, the release rate is typically a function of the active compound's concentration in the matrix.
U.S. Pat. No. 4,331,651 to Reul discloses a matrix device consisting of a silicone rubber depot for nasal administration to cattle. The rubber contains a "release promoting agent" which is liposoluble, scarcely soluble in water, and which may be an alcohol, ester, ether or ketone of 8-60 carbons. The active compound is a steroid, optionally an antibiotic. Preferred steroids are testosterone and trenbolone acetate, optionally in combination with estrogens such as 17.beta.-estradiol and its derivatives.
Matrix implants are also disclosed in P. J. Dziuk, et al., Am. J. Vet. Res. 29, 2413-2417 (1968) "Inhibition and Control of Estrus and Ovulation in Ewes with a Subcutaneous Implant of Silicone Rubber Impregnated with a Progestogen"; L. Beck, et al., Drugs, 27, 528-547 (1984) "Controlled-Release Delivery Systems for Hormones"; R. Heitzman, J. Animal Sci., 57, 233-238 (1983) "The Absorption, Distribution and Excretion of Anabolic Agents"; J. Wagner, et al., J. Animal Sci., 58, 1062-67 (1984) "Effect of Monensin, Estradiol Controlled Release Implants and Supplement on Performance in Grazing Steers"; N. Scheffrahn, et al., J. Animal Sci., 51, 108-109, "Induction of Male Sex Behavior in Ewes Using Silastic Implants Containing Testosterone Propionate."
Surface erosion is the major mechanism of delivering the actives to a mammal in a matrix-type implant. By applying a layer of water insoluble film around the implant, the release rate of the actives could be regulated. Such implants are known as "reservoir" type and consist of a central reservoir of active compound surrounded by a rate controlling membrane. This approach requires an adequate diffusion rate of the actives through the membrane.
The membrane may be either porous or non-porous, but is not usually biodegradable. It is typically easier to prepare a reservoir implant capable of zero order kinetics (independent of active compound concentration), as the release rate often depends only on the surface area of the membrane. However, reservoir devices often suffer from an inadequate rate of delivery given that the membrane surface area required to maintain an effective concentration of active compound is frequently so large that it is impractical to administer the implant. Reservoir implants are sensitive to rupture and an excessive, possibly lethal, dose of active compound may be released instantaneously.
Some sustained release devices are hybrids, having a matrix core surrounded by a rate controlling membrane. Other sustained release devices may be mechanical in nature, and include small compound-filled electrical or osmotic pumps. While these devices may be capable of zero order release, they are typically too expensive to compete economically with matrix and reservoir devices.
UK Patent Application 2,010,676 to Wong, et al. discloses a reservoir implant in the form of a flat, heatsealed packet, cylindrical tube or "T" vaginal insert, comprising a rate controlling membrane, specifically ethylene-vinyl acetate copolymer or butylene terephthalate/polytetramethylene ether terephthalate. The active compound is presented in a carrier which is water-imbibing (to maintain, but not increase the size of the implant), and viscous to improve drug distribution within the implant. These implants are useful for administering progesterone, estradiol, or d-norgestrel.
Other reservoir implants are disclosed in L. Beck, et al., "Controlled-Release Delivery Systems for Hormones" Drugs, 27, 528-547 (1984); W. Greene et al., "Release Rate of Testosterone and Estrogens from Polydimethylsiloxane Implants for Extended Periods In Vivo Compared with Loss In Vitro" Int. J. Fertil, 23, 128-132 (1978); E. Sommerville, et al., "Plasma Testosterone Levels In Adult and Neonatal Female Rats Bearing Testosterone Propionate-Filled Silicone Elastomer Capsules for Varying Periods of Time" J. Endocr., 98, 365-371, (1983); U.S. Pat. Nos. 4,210,644; and 4,432,964.
UK Patent Application 2,154,138A to Roche discloses a hybrid subcutaneous implant for livestock weight promotion, using silicone rubber with estradiol dispersed in the rubber. The implant is formed as a substantially hollow cylinder of the silicone rubber, with a core consisting of active ingredients (which may be steroids) dispersed in a biocompatible, biosoluble polymer which dissolves within days of implantation. The biocompatible, biosoluble polymer is a mixture of high and low molecular weight polyethylene glycol (PEG). For example, PEG 3,000-10,000 can be used with PEG 200-600. Thus, estradiol is released as if from a matrix (the silicone rubber wall), while the second active compound is released from a reservoir.
U.S. Pat. No. 3,992,518 to Chien discloses another hybrid implant comprising a membrane-wrapped silicone rubber matrix. The rubber matrix is prepared by forming an emulsion of rubber monomer and active compound in aqueous solution with a hydrophilic co-solvent, then crosslinking the monomer to form "microsealed compartments" containing the active compound in solution. The resulting matrix is then coated with a rate-controlling membrane. The rate-controlling membrane may be silicone rubber, ethylene/vinyl acetate, polyethylene terephthalate, butyl rubber, etc. The active compound is in a solution of water and a hydrophilic cosolvent not soluble in the rubber matrix. The hydrophilic cosolvent may be polyethylene glycol, propylene glycol, butylene glycol, etc., with PEG 400 preferred at a concentration of 20-70%. Active compounds disclosed include ethynodiol diacetate, ethylnyl estradiol, estrone, estradiol, other estrogens, progesterone, and testosterone.
U.S. Pat. No. 5,342,622 to Williams et al. discloses a pharmaceutical or veterinary implant comprising a peptide or protein and an excipient encased within a polymeric coating which is permeable and swellable. The coat forms a release rate limiting barrier and is preferably a neutral copolymer based on poly(meth) acrylic acid esters. One such suitable coating is "Eudragit E30D" (available from Rohm Pharma, GmbH).
U.S. Pat. No. 5,091,185 to Castillo et al. discloses a coated veterinary implant comprising a solid core of a growth hormone and a coating of polyvinylalcohol continuously enveloping the core.
U.S. Pat. No. 4,666,704 to Shalati et al. teaches an implant composition comprising (i) a core of a macromolecular drug and a water insoluble polymer and (ii) a pore-forming membrane with uniformly distributed pore-forming agent such as dimethyl and diethyl tartrate and lower partial esters of citric acid.
The mode of administration is usually critical to the design of a sustained release implant. The implant must be adapted to the appropriate biological environment in which it is used. For example, a device for subcutaneous implantation must be non-irritating, mechanically strong to withstand flexion or impact, and should provide long term delivery of the drug. In contrast, a device for oral administration must be designed for resistance to gastric acidity and sensitivity to pH change and short term delivery of drugs. Coatings suitable for gastric environments of acid pH that provide short term delivery of drugs, are known in the art. For example, Munday and Fassihi, Int. J. Pharm, 52: 109-114 (1989) disclose an oral control delivery tablet coated with insoluble polymers such as Eudragit RS and RL and a pore forming agent PEG 1540. This coating allows for 100% drug release within 10 hours after administration. Similarly, Marini et al., Drug Dev. Ind. Pharm, 17:865-877 (1991) and Muhamed et al., Drug Dev. Ind. Pharm, 17:2497-2509 (1991) disclose oral dosage forms comprising a coating with PEG. Both references show that such coating allows drug delivery within hours after administration.
It has now been surprisingly discovered that coatings containing PEG can be successfully used to make long term sustained release drug implants. Such PEG coatings unexpectedly increase the life of implants. For example, most cattle implants on the market have the release duration between 60-90 days. In order to continue promoting the growth of an animal, reimplantation of another dose is essential. R. L. Preston and J. R. Rains, FEEDSTUFFS, January 1993, pp. 18-20. Using implants prepared according to the present invention, the life of implants can be extended to over 150 days thus eliminating the need for repeated implantation. Another advantage of the coating technology of the present invention is that it offers a simple way of extending the duration of an implant without dramatic re-formulation of existing products and excessive costs. A third advantage to the present invention is that by varying amount of pore forming agent, the duration of the implant may be tailored to the desired target.